Keywords:
Stroke - Ischemic Stroke - Thrombectomy - Mechanical Thrombolysis - Thrombolytic Therapy
Palavras-chave:
Acidente Vascular Cerebral - AVC Isquêmico - Trombectomia - Trombólise Mecânica -
Terapia Trombolítica
INTRODUCTION
Acute ischemic stroke treatment has been one of the neurology subjects with the most
advances in recent years and with the greatest volume of evidence from well-designed
randomized clinical trials and extensive guidelines. However, a multitude of not uncommon
clinical scenarios have not been properly addressed in the trials and evidence-based
guidance on how to manage reperfusion therapies in the hyperacute setting is still
lacking in these situations. The objective of this article is to perform a review
of the current evidence regarding reperfusion therapy in controversial scenarios and
make suggestions that could help the decision-making process in some of these challenging
situations.
ENDOVASCULAR THROMBECTOMY IN LOW ASPECTS
ENDOVASCULAR THROMBECTOMY IN LOW ASPECTS
Most of the clinical trials that have demonstrated endovascular thrombectomy’s (EVT)
benefit in anterior circulation ischemic stroke used ASPECTS (Alberta stroke program
early computed tomography score) to select patients and were selective, excluding
patients with a score < 6 and presumably a greater core volume. Therefore, little
data regarding this population is available from the studies included in the HERMES
collaboration[1].
Although the MR CLEAN trial did not use ASPECTS or ischemic core volume as an exclusion
criterion, the median ASPECTS in the study was 9 (IQR 7-10), only 28 (5.6%) out of
496 patients had an ASPECTS < 5 and 120 (24.2%) < 8[2].
A pre-specified (but not registered) meta-analysis from the HERMES collaboration that
used individual data from seven clinical trials showed a benefit for patients with
ASPECTS 3-5, with 30/98 (31%) of EVT group patients achieving a modified Rankin Scale
(mRS) of 0-2 at 90 days compared to 14/90 (16%) of the control group (adjusted OR
4.27 [1.62-11.25]), but no benefit for patients with ASPECTS 0-2. Despite the supposed
benefit, thrombectomy yielded a greater risk of symptomatic intracranial hemorrhage
(sICH), present in 14/95 (15%) of the EVT group and 3/87 (3%) of the control group
of patients with ASPECTS 3-5 (OR 4.84 [1.27-27.03]). Similar results of efficacy and
sICH were found within the group with initial involvement greater than one third of
the middle cerebral artery territory[3].
After more widespread adoption of stroke thrombectomy, several observational studies
were performed trying to assess this matter and they mainly suggest that thrombectomy
could confer a better functional outcome in three months compared to conservative
management, with some studies also suggesting lower mortality and craniectomy rates.
Despite that, some studies also showed augmented risk for symptomatic intracranial
hemorrhage[4]-[7]. One retrospective analysis of the German stroke registry also suggested higher
risk for sICH, as well as higher mortality in the EVT group and no difference in favorable
outcomes. However, a significant effect regarding recanalization status was shown,
with 15% of mTICI (modified Thrombolysis in Cerebral Infarction Scale) 0-2a achieving
a 90-day mRS 0-3 against 28-36% in mTICI 2b-3[8].
Two meta-analyses on the effect of EVT in patients with ASPECTS < 6 were performed,
the first including 17 studies and 1,378 patients[9], the second, nine studies and 1,196 patients[10]. Both suggested better functional outcomes at 90 days in the endovascular group
compared to best medical management, with 30.1% of the EVT group achieving an mRS
0-2 versus 3.2% of the medical group (P=0.001) in the first study[9] and 27.7% and 3.7% in the second study, respectively (P=0.001)[10]. Regarding sICH, they produced conflicting results, one suggesting lower odds in
EVT group (20% vs 31.7%, P=0.05)[9], while the other showed a trend towards higher rates (9.2% vs 5.5%, P=0.11)[10]. One of the meta-analyses produced some subgroup data, showing that patients younger
than 70 had higher rates of mRS 0-2 compared to older patients (40.3% vs 16.2%) and
that initial ASPECTS had a direct relation with 90-day mRS 0-2 (33.3% of ASPECTS 5,
22.1% of ASPECTS 4, 13.9% of ASPECTS 0-3)[9]. Despite these important findings, both meta-analyses had serious limitations: most
of the included studies were retrospective, not randomized and several lacked a control
group; heterogeneity was high for most studied outcomes; the definition of sICH was
variable among studies; ASPECTS could be determined using magnetic resonance imaging
(MRI) or computed tomography (CT) depending on the study.
Despite ASPECTS being used as a selection criterion in most trials and guidelines
until now, its use has great limitations, as each of the 10 predefined areas have
diverse volumes and eloquence and each point is deducted in a binary fashion, disregarding
the infarcted volume within each region, the degree of hypodensity and the eloquence
of unaffected areas within each ASPECTS region. Some studies have already showed that
the correlation of ASPECTS and core volume is limited[11] and the more focused analysis of eloquence and degree of involvement in each region
might play an important role in functional outcome and treatment effect[12].
A recent single center observational study showed that in patients with ASPECTS ?
5 and baseline infarct volumes ? 70 ml the outcome of mRS 0-2 at 90 days in patients
submitted to EVT was 38.9% against 18.8% of patients with volumes > 70 ml (P=0.04
after adjusted multivariate analysis)[13]. A post-hoc analysis of a HERMES collaboration meta-analysis that included 177 patients
with baseline large core (defined as 80-300 ml in diffusion-weighted MRI / CT-perfusion
or ASPECTS ? 5) suggested that in patients with cores 80-130 ml or ASPECTS 4-5, thrombectomy
was associated with functional improvement (OR 2.11 [95% CI, 1.08-4.09]), but that
could not be demonstrated in patients with cores > 130 ml or ASPECTS ? 3 (OR 1.75
[95% CI, 0.62-4.89]), in which EVT was also associated with possible worsening of
edema and greater midline shift in follow-up images[14]. Both studies, despite their limitations, reinforce the importance of evaluating
volumes and not only ASPECTS in the treatment decision.
Probably the best piece of evidence until now is the recently published randomized
clinical trial conducted in Japan (RESCUE-Japan LIMIT), which randomized 203 patients
with ASPECTS 3-5 to receive EVT or best medical care within six hours after they were
last known to be well or within 24 hours if there were no early changes in FLAIR (fluid-attenuated
inversion recovery) images. Patients had to have at least 6 points in the NIHSS, a
previous mRS ? 1, occlusion of internal carotid artery or M1 segment of middle cerebral
artery. ASPECTS could be measured either with CT or DW-MRI. No relevant baseline disparities
were seen between groups and in general the included patients consisted of moderate
to severe strokes: median NIHSS of 22, median ASPECTS of 3, median infarct volume
of 94 ml (IQR 66-152) in EVT group and 110 ml (IQR 74-140) in the medical care group.
The primary outcome of mRS 0-3 at 90 days was achieved in 31.0% of the endovascular
group and 12.7% in the medical care group (RR 2.43; 95% CI 1.35 to 4.37; P=0.002).
Any intracranial hemorrhage within 48 hours was significantly higher in EVT group
(58% vs 31.4% [RR 1.85, 95% CI 1.33-2.58, P<0.001]) and sICH was also numerically
higher, although not statistically significant (9.0% vs 4.9% [RR 1.84, 95% CI 0.64-5.29,
P=0.25]). The main limitations of the study are that treating physicians and patients
could not be blinded, the population consisted only of Japanese patients, alteplase
was used in a small percentage of patients (27%), the standard dose of alteplase used
in Japan is 0.6 mg/kg and almost 90% of ASPECTS were calculated using MRI, limiting
the applicability of the results to ASPECTS calculated using CT[15].
Besides achieving reperfusion of potentially salvageable and eloquent areas, other
mechanisms of possible benefit of EVT in large stroke patients might play an important
role, such as diminishing associated cerebral edema[7] and preserving vascular cells in the ischemic area, facilitating vascular and neural
repair[16].
With the existing evidence, EVT in patients with ASPECTS 0-2 seems to be futile, but
it might be a reasonable treatment option for patients with ASPECTS 3-5, especially
in the following situations: ASPECTS measured using diffusion-weighted MRI, ASPECTS
4-5, ischemic core volume < 130 ml (even better if < 70 ml), younger age, less edema
and spared eloquent areas in the baseline image. However, several controversies still
remain: the augmented risk of hemorrhagic transformation; no consensus about the best
image modality for optimal selection (CT, CT-perfusion, diffusion-weighted MRI or
novel techniques to measure established edema as baseline Net Water Uptake)[17]; the cost-effectiveness of the treatment, especially in a resource limited setting;
better definition of a cutoff volume or ASPECTS for which benefit would still be sustained;
establish the role of area eloquence analysis, age, collateral circulation status,
beyond other factors.
Several clinical trials of EVT in low ASPECTS/large core are ongoing, with more data
expected to be added in the next months/years ([Table 1]).
Table 1
Ongoing randomized clinical trials regarding main themes addressed in the article[80].
|
Study
|
Comparison
|
Estimated enrollment
|
Inclusion criteria
|
Primary outcome
|
Country/region
|
Estimated completion
|
|
Low ASPECTS / Large Core
|
|
LASTE (NCT03811769)
|
Thrombectomy vs medical care
|
450
|
ASPECTS (CT or DWI) 0-5 if <80 years or 4-5 if ≥ 80 years; < 7h from LKW; ICA (isolated
cervical occlusion excluded), M1 or M1-M2 occlusion
|
180-day mRS shift analysis / 90-day mortality
|
France
|
Feb/2022
|
|
SELECT-2 (NCT03876457)
|
Thrombectomy vs medical care
|
560
|
ASPECTS (CT) 3-5 and/or core volume ≥ 50 ml on CTP/DWI; < 24h from LKW; ICA or M1
occlusion
|
90-day mRS shift analysis / 90-day mRS 0-2
|
USA, Canada, Australia, New Zealand and Spain
|
Nov/2022
|
|
TESLA (NCT03805308)
|
Thrombectomy vs medical care
|
300
|
ASPECTS (CT) 2-5, < 24h from LKW, ICA (cervical excluded) or M1 occlusion
|
UW 90-day mRS
|
USA
|
Nov/2022
|
|
ANGEL-ASPECT (NCT04551664)
|
Thrombectomy vs medical care
|
488
|
ASPECTS (CT) 3-5 or core volume 70-100 ml on CTP/DWI in patients with >6h or <6h and
ASPECTS (CT) 0-2; > 24h from LKW; terminal ICA or M1 occlusion
|
90-day mRS
|
China
|
Nov/2022
|
|
TENSION (NCT03094715)
|
Thrombectomy vs medical care
|
665
|
ASPECTS 3-5 (CT or DWI); < 12h from LKW; M1/ICA occlusion
|
90-day mRS shift analysis
|
Europe and Canada
|
Sep/2024
|
|
Distal / medium vessel occlusion
|
|
DISCOUNT (NCT05030142)
|
Thrombectomy vs medical care
|
488
|
NIHSS ≥ 5; < 6h from LKW; primary occlusion of distal M2, M3, P1, P2, P3, A1, A2 or
A3
|
90-day mRS 0-2
|
France
|
Dec/2023
|
|
DISTALS (NCT05152524)
|
Thrombectomy vs medical care
|
168
|
Perfusion lesion (CTP or MRP) ≥ 10 ml; core (CTP or DWI) ( 50% of perfusion lesion;
NIHSS 4-24 or 2-24 if aphasia or hemianopia; <24h from LKW; disabling deficit; primary
non-dominant M2, M3, ACA, PCA occlusion and vessel diameter ≥ 1.5 mm; not eligible
for IVT
|
Successful reperfusion (CTP or MRP) and no sICH
|
Not informed (sponsored by a USA located company)
|
Aug/2024
|
|
DISTAL (NCT05029414)
|
Thrombectomy vs medical care
|
526
|
NIHSS ≥ 4 or disabling deficit; <6h from LKW or 6-24h from LKW if CT/CTP or DWI/FLAIR
mismatch present; M2, M3-M4, A1, A2, A3, P1 or P2 occlusion
|
90 day-mRS
|
Switzerland
|
Dec/2024
|
|
ESCAPE-MeVO (NCT05151172)
|
Thrombectomy vs medical care
|
530
|
ASPECTS ≥ 8; NIHSS > 5 or NIHSS 3-5 with disabling deficit; <12h from LKW; M2-M3 or
A2-A3 or P2-P3 occlusion; penumbra demonstrated by CTA/CT/clinical exam or CTP or
MRP or DWI/MRA/clinical exam
|
90-day mRS
|
50 sites, coordination center at University of Calgary
|
Aug/2026
|
|
Vertobrobasilar occlusion
|
|
BAOCHE (NCT02737189)
|
Thrombectomy vs medical care
|
318
|
pc-ASPECTS ≥ 6; NIHSS ≥ 6; 6-24h from LKW (isolated vertigo not considered); BA or
intracranial VA occlusion
|
90-day mRS 0-3
|
China
|
December 2022
|
|
ATTENTION (NCT04751708)
|
Thrombectomy vs medical care
|
342
|
pc-ASPECTS ≥ 6 (≥ 8 if ≥ 80 years); NIHSS ≥ 10; <12h from estimated time of BAO
|
90-day mRS 0-3
|
China
|
May 2023
|
|
POST-ETERNAL (NCT05105633)
|
TNK 0.25 mg/kg vs tPA 0.9 mg/kg (+/- EVT)
|
688
|
pc-ASPECTS ≥ 7; <24h from LKW; BA occlusion (partial or complete)
|
90-day mRS 0-1 or return to baseline mRS
|
Australia
|
December 2026
|
|
Low NIHSS with proximal occlusion
|
|
MOSTE (NCT03796468)
|
Thrombectomy vs medical care
|
824
|
ASPECTS ≥ 6; NIHSS ( 5; < 24h from LKW; ICA, M1 or M1-M2 occlusion
|
90-day mortality
|
France
|
Feb/2022
|
|
ENDOLOW (NCT04167527)
|
Immediate thrombectomy vs initial medical care
|
200
|
ASPECTS ≥ 6; NIHSS ( 5; < 8h from LKW; ICA, M1 or “M1-like” M2 occlusion
|
90-day mRS ordinal shift analysis and sICH
|
United States
|
Jan/2023
|
A1: indicates first segment of anterior cerebral artery; A2: second segment of anterior
cerebral artery; A3: third segment of anterior cerebral artery; ASPECTS: Alberta stroke
program early computed tomography score; BA: basilar artery; BAO: basilar artery occlusion;
CT: non-contrast computed tomography; CTA: computed tomography angiography; CTP: computed
tomography perfusion; DWI: diffusion-weighted magnetic resonance imaging; FLAIR: fluid-attenuated
inversion recovery magnetic resonance imaging; ICA: internal carotid artery; IVT:
intravenous thrombolysis; LKW: last known well; M1: first segment of middle cerebral
artery; M2: second segment of middle cerebral artery; M3: third segment of middle
cerebral artery; M4: fourth segment of middle cerebral artery; MRA: magnetic resonance
angiography; MRP: perfusion magnetic resonance imaging; mRS: modified Rankin scale;
NIHSS: National Institutes of Health Stroke Scale; P1: first segment of posterior
cerebral artery; P2: second segment of posterior cerebral artery; P3: third segment
of anterior cerebral artery; pc-ASPECTS: posterior circulation acute stroke prognosis
early computed tomography score; sICH: symptomatic intracerebral hemorrhage; VA: vertebral
artery.
ENDOVASCULAR THROMBECTOMY FOR MEDIUM AND DISTAL VESSEL OCCLUSION
ENDOVASCULAR THROMBECTOMY FOR MEDIUM AND DISTAL VESSEL OCCLUSION
Occlusion of the middle cerebral artery (MCA) after its first bifurcation (although
not anatomically accurate, the majority of thrombectomy trials considered this as
M2 segment, so we will use this same terminology in this article) was excluded from
most EVT randomized clinical trials, as well as anterior cerebral artery (ACA) and
posterior cerebral artery (PCA) occlusions. Some of the trials included M2 occlusions,
but they were under-represented and were mainly proximal and dominant trunks, functionally
similar to M1 occlusions[18].
Therefore, EVT for medium/distal vessels lacks support from studies with good evidence,
despite the high prevalence of occlusion of these vessels in initial imaging (primary
occlusions) accounting for 25-40% of strokes[19] and also as a complication of large vessel occlusion treatment (secondary occlusion),
either to the same territory of the initial large vessel (incomplete reperfusion was
found in 80% of HERMES collaboration trials)[20] or to a new territory (9.4% of internal carotid artery [ICA]/MCA thrombectomy complicates
with ACA embolization)[21].
As opposed to what is expected from proximal (ICA/M1) occlusion, distal vessel involvement
confers a great heterogeneity of clinical presentations, as different territories
are considered (ACA, MCA or PCA) and even when the same artery is occluded in two
patients, due to great anatomic variability of distal vessels and collateral circulation,
the functional and clinical importance of the occlusion can be diverse.
The occlusion diagnosis can be inferred as a dot sign in CT or MRI susceptibility
vessel sign, confirmed when a cutoff can be shown in CT/MRI angiography. These signs
can be more easily identified in the more proximal segments (M2, P1, A1), but can
be difficult to find in more distal vessels and when there is a trifurcation or other
anatomic variability, situations in which perfusion imaging can greatly improve sensibility
to 80-100%[22], as well as inform if the territory of the occluded artery is still viable. In the
absence of perfusion imaging, a clinical deficit consistent with the occluded artery
with a clinical/core (diffusion-weighted MRI) mismatch can also be indicative of viable
tissue.
While smaller territories are at risk when compared to proximal occlusion (ICA/M1),
a great proportion of patients remain functionally dependent (mRS >2): 60% of M2[23], 70% of P1 and 44% of P2 occlusions[24]. ACA isolated occlusions were associated with 49% of patients moving to chronic
care facilities or mRS >2[25] and ACA embolization during ICA/M1 EVT conferred significant lower rates of 90-day
mRS 0-2 (25% vs 48% [adjusted OR 0.48, 95% CI 0.25-0.92, P=0.027])[21]. Early recanalization after intravenous thrombolysis, despite greater than for ICA/M1
occlusion, are unsatisfactory, being achieved only in 37-44% of M2[26],[27], 52% of M2-M3[28] and 42% of M3/ACA/PCA occlusions[27], justifying the study of alternative treatments, as EVT.
Due to greater distance, increased tortuosity and smaller diameters in more distal
vessels, EVT poses more technical challenges and risks (dissection, perforation, vasospasm,
embolization to new territories) when compared to proximal occlusions, but endovascular
technology has advanced with smaller/low profile stent retrievers and aspiration catheters
that are suitable for distal vessels[29]-[30].
The HERMES collaboration analyzed the data from 130 patients with M2 occlusion included
in the pivotal EVT trials and found a TICI 2b-3 recanalization in 59.2% of patients
and 90-day mRS 0-2 in 58.2% of EVT group against 39.7% in control group (adjusted
OR 2.39 [95% CI 1.08-5.28, p=0.03]). Treatment effect favoring EVT was maximal in
proximal and dominant M2 (adjusted OR of 2.68 and 4.08, respectively)[18]. Thrombectomy with stent retrievers and aspiration catheters has shown comparable
results for M2 occlusions in more recent studies, with a TICI 2b-3 recanalization
rate above 80%[31].
Small (n=69 and 130) single center observational studies of EVT for M3-M4, ACA and
PCA occlusions (distal MCA cases were majority) showed that the procedure is feasible
and safe, with satisfactory recanalization in 75-83% of cases, with similar results
between primary and secondary occlusions and relevant intraparenchymal bleeding in
7-8% of cases[32],[33]. In one of the studies, which used several techniques (stent-retriever in 54%, aspiration
in 45% and intra-arterial recombinant tissue plasminogen activator [rtPA] in 52%),
the rate of 90-day mRS 0-2 was 30% (38-54% for M3), but strokes were moderate/severe,
with median baseline NIHSS of 18 (IQR 13-23) and mortality of 20%[32].
A multicenter case-control study of EVT for primary distal PCA (P2-P3) occlusion (TOPMOST)
showed a mTICI 2b-3 recanalization rate in 87.4% of cases using several techniques
(stent-retriever +/- aspiration in 72%, primary aspiration in 26% and intra-arterial
rtPA in 1.4%). Among 184 matched patients, EVT conferred a non-significant better
result in median NIHSS decrease at discharge (mean difference -1.5 [95% CI 3.2 to
-0.8; P=0.06]), with significant results shown in subgroup analysis of NIHSS ≥ 10
(mean difference −5.6 [ 95% CI −10.9 to −0.2; P=0.04) and patients not submitted to
intravenous rtPA (mean difference −3.0 [95% CI −5.0 to −0.9; P=0.005). Although the
favorable results of NIHSS decrease at discharge, no difference was shown for 90-day
mRS 0-2 (76.6% vs 75.4%, P=0.87). Regarding safety concerns, there was no difference
in sICH (4.3% in both groups, P>0.99) or mortality (11.8% vs 15.8%, P=0.40). Median
baseline NIHSS in this study was 5 (IQR 3-10)[34].
Small (n=41 and 30) single center observational studies of EVT (83% with stent-retriever)
for distal ACA occlusions also showed good mTICI 2b-3 rates (83-88%) and low rates
of complications, with 10% of asymptomatic regional subarachnoidal bleed described
in one series and 10% of vasospasm and 3.3% of asymptomatic hemorrhagic transformation
in ACA territory in the other. Initial NIHSS was high (mean of 17-18) and 90-day mRS
0-2 was achieved in only 20-36% of patients, but almost all were associated with ICA/M1
occlusion, limiting the interpretation of these outcomes[35],[36].
Although several studies indicate that thrombectomy for distal occlusion is safe and
viable, only a few studies have compared its efficacy to intravenous rtPA. One meta-analysis
of four retrospective observational studies (with significant heterogeneity [I[2]=89%]) with 381 patients with A2, M3-M4 or P2-P4 occlusion did not demonstrate a
significant difference in 90-day mRS 0-2 between the groups (OR 1.16, 95% CI 0.23-5.93;
P=0.861)[37].
Currently there is very limited evidence, mainly from observational studies, regarding
endovascular thrombectomy to distal and medium vessels occlusion, making it not possible
to make general recommendations about its clinical effectiveness in comparison with
best medical care. In selected cases, considering the relative safety and high recanalization
rates of present-day endovascular techniques, a multi-specialty (stroke neurologist,
neuroradiologist and neurointerventional radiologist) individualized approach could
be sought, taking several factors into consideration: more proximal occlusions (A1,
P1 and M2 - especially if the occluded M2 is dominant, for which there is some subgroup
favorable data from randomized clinical trials), higher baseline NIHSS or disabling
deficits, presence of relevant penumbra-core or clinical-core mismatch in eloquent
locations, contraindication to intravenous thrombolysis (IVT) as factors in favor
of EVT; and difficult proximal access, more tortuous vasculature, lower baseline NIHSS
with no disabling deficits, greater proportion of core in the involved territory as
factors against it. A lot of questions still need to be addressed, as the use of advanced
imaging techniques in selection of patients; the role of intra-arterial rtPA, which
was demonstrated to be safe[38] and with some exciting good clinical results in a recent randomized trial suggesting
the importance of distal circulation reperfusion[39]; what the factors are for achieving a relevant treatment effect; among others. Despite
the difficulty of designing randomized clinical trials due to great clinical heterogeneity,
several are under way and some answers are expected in the future ([Table 1]).
ACUTE BASILAR ARTERY OCCLUSION
ACUTE BASILAR ARTERY OCCLUSION
Acute ischemic stroke due to basilar artery occlusion (BAO) represents 20% of posterior
circulation strokes and 1-4% of all ischemic strokes[40],[41]. BAO is one of the most challenging emergencies with death rates up to 80-90% in
the absence of therapeutic interventions. The clinical picture of BAO varies greatly,
with 30-60% of patients presenting with coma, tetraplegia or locked-in syndrome[41]. In the majority trials of stroke reperfusion, BAO and posterior circulation stroke
are underrepresented[40]. Optimal reperfusion strategies are still under discussion.
The Basilar Artery International Cooperation Study (BASICS) registry, an observational
prospective multicenter study, reported a 10-19% absolute lower death rate and dependency
for severe patients with acute BAO treated with intravenous thrombolysis (IVT) or
EVT, compared to therapy with antiplatelet or anticoagulant drugs. Yet death ranged
from 40% to 50% in patients submitted to IVT and EVT, with 6% of sICH in IVT group[42].
The reverse filling of the distal basilar artery by posterior communicating arteries
and the abundant collaterals from posterior circulation collaborate to brainstem ischemic
resistance. It has been suggested that as long as perforators are patent, brainstem
can be viable for a long period. The small infarct cores compared with anterior circulation
contribute to resistance to hemorrhagic transformation in the brainstem[43]. Based on these hypotheses, IVT has been simultaneously or immediately followed
by anticoagulation in BAO for more than 20 years by a group from Helsinki in patients
up to 12 hours after the sudden onset of neurological deficits or up to 48 hours of
progressive neurologic deficits[44]. The Helsinki group reported that, in 207 patients treated with IVT and anticoagulation,
favorable outcomes of mRS 0-3 were achieved in 41.1% and mRS 0-2 in 31.3% at three
months. The recanalization rate was around 70% and sICH, 11.4%[45]. However, there is no evidence based on randomized clinical trials that add-on anticoagulation
is beneficial in acute BAO.
EVT has led to dramatic changes in anterior circulation stroke treatment and a meta-analysis
of 45 studies and 2056 patients concluded that recanalization has a significant effect
on BAO outcomes (number needed to treat of 2.5 to prevent death and disability)[46]. Rates of recanalization up to 80-100% can be achieved after EVT in BAO. Yet, no
striking benefit has been achieved in the latest randomized trials of EVT in BAO.
Reasons that may justify this are the slow recruitment, lack of a criteria for patient
selection such as in anterior circulation, lack of equipoise, as there are several
reports of a favorable outcome with EVT in retrospective and observational trials,
so physicians may consider it is not appropriate to randomize these patients anymore.
An open label, randomized trial (BEST) of EVT up to eight hours after the estimated
onset of BAO was stopped prematurely due to a high crossover rate (22%) and drop in
recruitment, probably due to loss of equipoise. The study’s primary endpoint analysis
failed to show a difference in the proportion of patients with favorable neurologic
outcomes (90-day mRS 0-3 of 42% in the intervention group vs 32% in controls [adjusted
OR 1.74; 95% CI 0.81-3.74]) despite 71% achieving successful reperfusion. After accounting
for the effects of crossover, there were higher rates of favorable outcome in patients
who received intervention compared to control in the as-treated population, 47% vs
24% (adjusted OR 3.02; 95% CI 1.31-7.00). A higher incidence of sICH in the intervention
group was documented (8% vs 0), however mortality was similar (33% in intervention
vs 38% in control)[47].
BASILAR, a nonrandomized study, suggested that EVT (n=647) may be safe and effective
up to 24 hours after the estimated onset of BAO, when compared to control (n=182).
EVT was associated with a significantly higher rate of 90-day mRS 0-3 (adjusted OR
4.70; 95% CI 2.53-8.75) and a lower mortality rate at 90 days (adjusted OR 2.93; 95%
CI 1.95-4.40) despite an increase in sICH (7.1% vs 0.5%)[48].
BASICS, a randomized trial of EVT up to six hours after the estimated onset of BAO,
failed to demonstrate an overall benefit of EVT compared with control. The primary
endpoint of favorable functional outcome (mRS 0-3) at 90 days was not significantly
different between the groups of EVT (44.2%) and control (37.7%). In subgroup analysis,
patients with NIHSS ≥10 had significantly more benefit if treated with EVT. EVT group
sICH rate was 4.5%. The slight benefit of EVT in BASICS trial might be related to
the overwhelming effect of IVT, administered to 80% of the patients and selection
bias of patients to be randomized[49]. Comparisons between BASICS, BASILAR and BEST trials are limited by patient heterogeneity,
differences in medical treatment (20-30% of IVT in BEST and BASILAR) and different
time spans allowed for reperfusion. A Bayesian meta-analysis of both randomized trials
and a patient-level meta-analysis of NIHSS ≥ 10 from both trials suggested significantly
improved outcomes in the EVT arm[50],[51].
Relevant variables may influence BAO outcome. These are: onset time to treatment,
age >60 years, higher NIHSS and Glasgow coma scale scores at admission, failure to
recanalize and collateral circulation[52]-[54]. Embolic etiology may also be associated with worse outcomes. Nevertheless, higher
recanalization rates have been reported with embolic occlusion than with in situ atherosclerotic
thrombosis in BAO[55]. The site of occlusion has also has prognostic implications when treated, and distal
lesions have better outcomes than proximal ones[56].
The extent of ischemia can be assessed with the posterior circulation acute stroke
prognosis early CT score (pc-ASPECTS)[57]. Patients with pc-ASPECTS <8 typically have worse functional outcomes than those
with higher scores, despite recanalization. However, others found that lower thresholds
of pc-ASPECTS (≥5) are also associated with a good outcome[58]-[60]. In patients with pc-ASPECTS ≥8, the time to treatment may not influence outcomes[44]. In addition, in the ETIS study[59], a time-dependent benefit was found in patients with pc-ASPECTS <8. In BASICS registry[54], most of the benefit of reperfusion therapies was time-dependent, no severe patient
after nine hours of estimated BAO achieved a favorable outcome. The pc-ASPECTS has
been criticized by its interrater variability, need for expertise in scoring, and
limitations of assessment of the posterior fossa on CT[57].
Besides pc-ASPECTS, cerebellar infarct volume also seems to be an independent predictor
for 90-day mortality. It is known that cerebellar mass effect due to infarction and
edema may lead to hydrocephalus and brainstem compression. It is one of the important
causes of death in acute BAO patients. In one study, risk of death was increased for
baseline volume ≥4.7 ml[61].
Collaterals and thrombus burden are an important predictor of clinical outcomes in
anterior and posterior circulation strokes. BATMAN is a 10-point scoring system that
includes these characteristics and is considered a predictor of functional outcome
in BAO[62]. Higher BATMAN score means shorter thrombus and/or better collaterals. Reperfusion
was associated with a good outcome in those with favorable BATMAN score (≥7), despite
time to treatment <6 or >6 hours. Yet, in patients with unfavorable BATMAN, time to
treatment <6 hours was significantly related to good outcomes[52].
There are many reports of patients with BAO, low pc-ASPECTS, long onset to treatment
time (>24 hours) and severe presentation with favorable functional outcomes after
reperfusion treatment and intensive rehabilitation. This is an additional dilemma
for decision-making because despite a predicted unfavorable prognosis, some patients
can achieve functional independence[63],[64]. Therefore, physicians must be cautious with the self-fulfilling prophecy in BAO
therapy decisions.
Therefore, against a life-threatening condition such as BAO, the best choice is an
individualized therapy for each patient. Neurologists should decide on the type of
treatment combination (IVT, EVT, add-on anticoagulation or no reperfusion therapy)
based on clinical features (age, NIHSS, Glasgow Coma Scale), radiological appearance
(infarct core, pc-ASPECTS, BATMAN, cerebellar infarct volume, site of occlusion),
onset time to treatment, stroke mechanism and risk of sICH. The better the combination
of these characteristics probably the better the outcome will probably be. If the
combination of the variables does not seem favorable, most likely the recanalization
will be futile.
The next studies in BAO should focus on how to adequately select patients who can
have a substantial treatment effect and achieve good outcomes.
PROXIMAL OCCLUSION WITH LOW NIHSS SCORES
PROXIMAL OCCLUSION WITH LOW NIHSS SCORES
Patients with mild strokes can worsen after initial evaluation, mainly secondary to
ischemic complications probably due to failure of collateral circulation and the presence
of proximal occlusion is an independent predictor for this adverse scenario[65]. Around 10% of patients with baseline NIHSS <6 have proximal occlusion detected
on CT/MRI angiography and 20% have clinical deterioration ≥ 4 point on NIHSS, usually
early after hospital arrival (median of 3.6h [IQR 1-16h]), causing worse functional
outcomes[66]. Therefore, these patients should be transferred for an EVT-capable center and closely
monitored.
Thrombectomy trials included in HERMES collaboration included a small number of patients
with NIHSS ? 10 and subgroup analysis for this population was not powered to show
benefits from EVT[1]. Until now, there are no randomized trials on this topic and observational evidence
is divergent.
Some multicenter observational studies found no difference in functional outcomes
between EVT group and best medical care group, with a higher risk of sICH in EVT group.
However, in these studies, there was no differentiation if patients received immediate
EVT on admission or rescue EVT (performed only after clinical deterioration); both
were included in the EVT group and the prognosis of patients that have clinical deterioration
is known to be worse. In the studies in which IVT to EVT time was available, median
time was much longer than would be expected[67],[68]. In a planned randomized trial, patients that received initial medical care followed
by rescue EVT would be considered as being part of the medical care group.
A multicenter retrospective study considered this important factor in its analysis,
including 80 patients in the immediate EVT group and 220 patients in the medical care
group, of which 25 (11.3%) received rescue EVT. Immediate EVT was an independent predictor
of mRS 0-2 (OR 3.1, 95% CI 1.4-6.9) with an absolute difference of 15% (85% vs 70%),
but conferred not statistically significant higher rates of sICH (5% vs 1.4%, P=0.08).
Matched analysis corroborated the results, with higher rates of 90-day mRS 0-2 in
the immediate EVT group (84.4% vs 70.1%, P=0.03) and not statistically significant
higher numbers of sICH (5.2% vs 2.6%, P=0.41)[69].
Despite current guidelines recommending against IVT in minor non-disabling strokes,
this recommendation was mainly based on the results of the PRISMS trial, in which
the rate of proximal occlusion was a minority[70]. Therefore, due to the increased risk of stroke progression in the patients with
proximal occlusion, IVT should still be considered.
A recent multicenter retrospective French study with 729 patients with large vessel
occlusion and NIHSS <6 that were treated with IVT showed that still after IVT ischemic
early neurological deterioration occurred in 12% of patients and was strongly associated
with poorer 90-day outcomes, even in patients who underwent rescue thrombectomy. This
cohort was used to elaborate a novel 4-point score for early ischemic neurological
deterioration prediction using the two factors that were independently associated
with it in multivariable analysis: a more proximal occlusion site (0 point for M2;
1 point for distal M1; 2 points for proximal M1 or tandem or basilar; 3 points for
terminal ICA) and longer thrombus (1 point if ≥ 9mm). The score was validated in another
cohort and showed good discriminative power. In both cohorts early deterioration probability
was approximately 3%, 7%, 20%, and 35% for scores of 0, 1, 2 and 3-4, respectively[71].
While the results of two ongoing randomized clinical trials are expected in the next
year to better guide reperfusion therapies ([Table 1]), in conjunction with the imaging features of the aforementioned score, some clinical
information that possibly indicates an unstable collateral circulation with higher
risk of imminent failure can be used to help in making clinical decisions, such as
deficit fluctuation, auto-hypertension and a stress test consisting of sitting the
patient upright for 10-20 minutes or even walking and observing for signs of clinical
deterioration. Some clinicians may also pursue surrogate measures of vascular reserve
such as transcranial doppler ultrasound or perform perfusion imaging to demonstrate
a possible territory at risk[72]. Although biologically plausible, all these alternatives lack proper validation.
INTRAVENOUS THROMBOLYSIS IN PATIENTS USING DOACS
INTRAVENOUS THROMBOLYSIS IN PATIENTS USING DOACS
In the last few years, there has been an increase in the number of patients taking
direct oral anticoagulants (DOACs). The American Heart Association guidelines recommend
against IVT in patients who have taken DOACs in the last 48 hours. However, there
have been successful case reports of patients receiving IVT after reversal of dabigatran
by idarucizumab[73]. Other reversal agents such as andexanet alpha have potential prothrombotic effects,
but its reversal effects are known to be less reliable, and the evidence is even scarcer.
A meta-analysis (with no heterogeneity, I[2]=0) of patients taking DOACs (n=366) that received IVT found no difference in sICH
compared to patients taking warfarin with international normalized ratio < 1.7 (n=2133)
or patients without prior anticoagulation (n=50324). In addition, last DOAC intake
time and use of pre-thrombolysis idarucizumab were not related with sICH[74]. However, randomized trials are still lacking and are not expected soon. Unaltered
drug-specific coagulation assays or thromboelastography could serve as a surrogate
for low DOAC activity and confer a better safety profile for thrombolysis, but these
are not readily accessible in a timely manner in most hospitals, validation for this
use has yet to be reported and patients with altered results would still be excluded
from treatment.
Factors that could counterbalance in favor of administering IVT would be a severe/debilitating
presentation, possibility of IVT in the first hours when benefit is maximal, absence
of other conditions that increase sICH risk, longer time from last DOAC administration
and normal drug-specific assays/thromboelastography. In patients with minor stroke,
EVT indication (where IVT bridging efficacy is under debate), high risk for sICH,
>3h from last known well and very recent use of DOAC, the risks would probably outweigh
the benefits of IVT. Further studies are urgently needed to access whether previous
DOAC use should be withheld as a contraindication in current guidelines, as has occurred
with several previous IVT contraindications. The development of more accessible point
of care coagulation tests for better selection of patients might also be a useful
strategy in the near future[75].
ENDOVASCULAR THROMBECTOMY AFTER 24 HOURS OF TIME LAST KNOWN WELL
ENDOVASCULAR THROMBECTOMY AFTER 24 HOURS OF TIME LAST KNOWN WELL
EVT up to 24 hours had a huge effect and shifted the traditional time window to tissue-based
evaluation for patient selection. A retrospective multicenter series demonstrated
similar outcomes in patients treated with more than 24 hours from time last known
well that otherwise met DAWN[76] criteria in comparison with patients in DAWN trial intervention group regarding
mTICI 2b-3 (81% vs 84%, P=0.72), 90-day mRS 0-2 (43% vs 48%, P=0.68) and sICH (5%
vs 6%, P=0.87). Median interval from time last known well to groin puncture was of
48 hours (IQR 30-72h)[77]. Another retrospective series of patients with more than 16 hours from time last
known well (median of 43.5h [IQR 23-77h]) where EVT was indicated at the discretion
of the clinician (n=24) showed favorable outcomes when compared to a propensity score-matched
data set with a higher proportion of 90-day mRS 0-2 (adjusted OR 11.08 [95% CI 1.88-108.60].
Although not statistically significant, DEFUSE-3[78] imaging criteria might have the potential to determine which patients benefit from
treatment[79].
There are probably few patients who are ultra-slow progressors due to enhanced collateral
circulation that still can benefit from EVT. Therefore, reperfusion strategies might
be considered as a possibility even in patients beyond 24 hours of time last known
well with small infarct core at presentation and who would otherwise be included in
DAWN or DEFUSE-3 criteria.
In conclusion, the strong evidence in favor of reperfusion therapies in the management
of acute ischemic stroke and its relevant impact on functional outcomes for some already
established situations have led to research as to whether other, not yet still well-studied
stroke populations could also greatly benefit from it. Fortunately, stroke research
keeps progressing with outstanding multicenter and coordinated efforts to advance
the boundaries of current knowledge, with exciting new data expected in the near future
([Table 1]).
